Modeling of glycosaminoglycan biosynthesis in intervertebral disc cells

Loss of proteoglycan (PG) is a potential factor responsible for degeneration of the intervertebral disc (IVD). PG consists of a core protein with covalently attached glycosaminoglycan (GAG) chains. The objective of this study was to develop a mathematical model of GAG biosynthesis to investigate the effects of glycolytic enzymes on GAG biosynthesis of IVD cells. A new mathematical model of GAG biosynthesis was developed for IVD cells by incorporating biosynthesis of uridine diphosphate-sugars into the glycolytic pathway. This new model showed good agreement between the model predictions of intracellular ATP content and GAG biosynthesis and experimental data measured at different external glucose levels. The quantitative analyses demonstrated that GAG biosynthesis may be sensitive to the activities of hexokinase (HK) and phosphofructokinase (PFK), especially at low glucose supply, with GAG biosynthesis being significantly enhanced by a slight increase in activities of HK and PFK. This suggests that metabolic reprogramming could be a potential strategy for promoting PG biosynthesis in IVD cells. Furthermore, it was shown that GAG biosynthesis may be promoted by increasing intracellular glutamine concentration or activity of glutamine:fructose-6-phosphate amidotransferase in the hexamine pathway. This study provides a better understanding of the relationship between glycolysis and PG biosynthesis in IVD cells. The theoretical framework developed in this study is useful for studying the role of glycolysis in disc degeneration and developing new preventive and treatment strategies for degeneration of the IVD.